Efficient synthesis of new polyfunctionalized thiadiazaacenaphthylenes from imidazo[1,2-a]pyridines

Article abstract of DOI:10.3987/com-01-9347

New heterocycles containing sulfur and nitrogen with an azaindolizine moiety were synthesized. The imidazo[1,2-a]pyridine-2,5-dicarboxylates (9a, b, 10a, b) and 5-formylimidazo[1,2-a]pyridine-2-carboxylates (17a, b) treated with ethyl thioglycolate and lithium hydroxide underwent ring closure yielding the multifunctional[2,3,3]cyclazines (13) and (18). Under similar conditions, the imidazo[1,2-a]pyridinecarbaldehydes (22a, b) and (29a, b) were converted into the linearly cyclized compounds thieno[3,2-b]imidazo[1,2-a]pyridines (23, 31) and a peri annulated product thiadiazaacenaphthylene (30).

Full text of DOI:10.3987/com-01-9347

HETEROCYCLES, Vol. 57, No. 1, 2002, pp. 21 - 38, Received, 25th September, 2001
EFFICIENT SYNTHESIS OF NEW POLYFUNCTIONALIZED THIA-
DIAZAACENAPHTHYLENES FROM IMIDAZO[1,2-a]PYRIDINES
Emmanuel Moreau,a Jean-Michel Chezal,a Caroline Dechambre,a Damien
Canitrot,a Yves Blache,b Claire Lartigue,a Olivier Chavignona and
Jean-Claude Teulade a*
a
UMR INSERM 484, Faculté de Pharmacie, 28 Pl. H. Dunant, B.P. 38, 63001 Clermont-Ferrand
b
CEDEX 1, France. Laboratoire de Chimie Organique Pharmaceutique, Faculté de Pharmacie,
15 Av. Ch. Flahault, 34060 Montpellier, France. Fax : (+33)4-73-17-80-12 ; e-mail : J-
Claude.TEULADE@u-clermont1.fr
Abstract-New heterocycles containing sulfur and nitrogen with an azaindolizine
moiety were synthesized. The imidazo[1,2-a]pyridine-2,5-dicarboxylates (9a, b,
10a, b) and 5-formylimidazo[1,2-a]pyridine-2-carboxylates (17a, b) treated with
ethyl thioglycolate and lithium hydroxide underwent ring closure yielding the
multifunctional[2,3,3]cyclazines (13) and (18). Under similar conditions, the
imidazo[1,2-a]pyridinecarbaldehydes (22a, b) and (29a, b) were converted into
the linearly cyclized compounds thieno[3,2-b]imidazo[1,2-a]pyridines (23, 31)
and a peri annulated product thiadiazaacenaphthylene (30).
INTRODUCTION
The skeleton of imidazo[1,2-a]pyridine (IP), an aza-analog of indolizine, is an important pharmacophore
for therapeutic drugs. IP compounds have been used to reduce neurotoxin injury associated with anoxia or
ischemia,1 and employed as antiviral agents,2 ligands for benzodiazepine receptors.3 More recently, the
development of methods for the regiocontrolled synthesis of multifunctional heterocycles has given
access to new compounds: in particular, works on IP fused at C(5)-C(3) have been extended to include
cyclazines,4 a tricyclic ring system.5 These triazaacenaphthylene compounds were shown to display
platelet-derived growth factor (PDGF) inhibitory activity.6 Thiadiazaacenaphthylenes have also been
successfully prepared.7 Our interest in annulation in IPs8 prompted us to study a synthetic approach to
obtain novel multifunctional cyclazines. In the course of our work using nitro-IP as a synthetic auxiliary,9
we previously described the nucleophilic aromatic substitution reaction by displacement of the nitro

group of some 3-nitro-IP with thioglycolate anion. We failed to complete the construction of the
cyclazine skeleton via a Dieckmann reaction (Scheme 1).10
Scheme 1
N
N
2
R1
R1
N
N
5
3
X
EtO2C
N
NH2
X
( )n
R2
R2
EtO2C
R1 = H, CHO, CO2Et
R2 = CHO, CO2Et
R1 = H, CHO, CO2Et
R2 = H, OH
X = O, S
X = Br, NO2
n = 0, 1
In continuation of our work on novel cyclazine synthesis, we focused on 2-, 3- and 5-functionalized IPs.
In addition, when the introduction of functional groups (ester, formyl) into the 5-position of IP was tried,
a peri annulation took place under mild conditions. We detail here a new synthetic approach to the
construction of imidazopyridothiazines for screening as potential immunostimulants.
RESULTS AND DISCUSSION
Starting material ethyl 2-aminopyridine-6-carboxylate (1) was readily prepared from commercially
available 2-amino-6-methylpyridine via N-acetylation, oxidation, deacetylation, and esterification by
reported procedures11 (Scheme 2).
Scheme 2a
N
N
2
X
N
iii or iv
CO2Et
4a, b
i
N
EtO2C
N
NH2
N
3
R
2 : R = CO2Et
3 : R = CHO
N
1
ii
X
a: X = Br
b: X = NO2
CHO
5a, b
N
v
N
4a, b or 5a,b
X
X
R
R = H, OH
X = O, S
CO2Et
aReagents and conditions: (i) ClCH2CHO, EtOH, reflux; (ii)
DIBALH, -70 °C, THF; (iii) Br2, AcOH, rt; (iv) H2SO4, HNO3, rt; (v)
HOCH2CO2Et, HSCH2CH2CO2Et or HSCH2CO2Et (1 equiv.),
LiOH (2 equiv.), DMF, -10 °C.

The compound (1)11 reacted with chloroacetaldehyde in refluxing ethanol to afford the imidazopyridine
(2), which was converted to the corresponding aldehyde (3) under Yamanaka’s conditions.12 The
bromination of 2 and 3 (bromine in AcOH) or the nitration (H2SO4/HNO3) at room temperature gave 3-
bromo- and 3-nitro-IP (4a, 5a) and (4b, 5b) respectively13 (see general details in EXPERIMENTAL).
Compounds (4a, b) were treated in dry DMF with an equivalent of ethyl glycolate (or ethyl 3-
mercaptopropionate or ethyl thioglycolate) and an excess of lithium hydroxide9, 14, 15 but the expected
tricyclic ester was not obtained and the starting material was recovered. Similarly, 5a, b were also
recovered unchanged even after two days at low and room temperature.
However, the presence of an electon-withdrawing group in position 2 promotes the substitution of iodo-
or nitro groups at position 3 of IP.9, 16 Accordingly, we investigated the reactivity of the diesters (9a, b
and 10a, b), readily obtained in two steps from the esters (1)11 and (6),11 respectively (Scheme 3).
Scheme 3a
N
N
i
ii or iii
CO2Et
CO2Et
N
N
R
N
NH2
X
R
R
9a, b: R = CO2Et
10a, b: R = CO2Me
7: R = CO2Et
8: R = CO2Me
1: R = CO2Et
6: R = CO2Me
N
CO2H
NO2
iv
N
9b
9b
CO2Et
11
a: X = Br
b: X = NO2
N
CO2Et
2
v
N
S
CO2Et
12
N
vi
9a, b or 10a, b
N
CO2Et
S
HO
CO2Et
13
aReagents and conditions: (i) BrCH2COCO2Et, EtOH, reflux; (ii) Br2,
AcOH, rt; (iii) H2SO4, HNO3, rt; (iv) HOCH2CO2Et (1 equiv.), LiOH (2
equiv.), DMF, -10 °C; (v) HSCH2CH2CO2Et (1 equiv.), LiOH (2 equiv.),
DMF, -10 °C; (vi) HSCH2CO2Et (1 equiv.), LiOH (2 equiv.), DMF, -10 °C.

After treatment of 9b with ethyl glycolate anion in DMF, the product was not the annulated tricyclic
compound but the acid (11). When 9b was allowed to react with ethyl 3-mercaptopropionate in DMF
containing lithium hydroxide under cooling in ice-bath, we isolated the corresponding disulfide (12). A
reasonable explanation for the formation of compound (12) would be a β-elimination in the basic
medium, giving the arylthiol anion which attacks another compound (9b).15 Also, when 9a, b were
allowed to react with an equivalent ethyl thioglycolate and excess lithium hydroxide in DMF, the product
was the expected diethyl 5-hydroxy-3-thio[1,8-b]diazaacenaphthylene-2,4-dicarboxylate (13). The
1
13
structure of the cyclazine (13) was supported by H and C NMR spectra. The analysis of INEPT data
between H-6 (δ 7.00) and C-5 (δ 163.1), methylene proton signals at δ 4.12 and 4.26 and the carbonyl
carbons of esters (δ 162.5 and 166.0) showed that the cyclization took place on the 5-ester group of
compounds (9, 10) by peri annulation. This structure was further confirmed by the same reaction of 10a,
b in LiOH/DMF. Disappearance of the 5-COOMe and 3-Br (or 3-NO2) groups in compounds (10a, b)
supported that the cyclization was a peri annulation. A similar reaction was performed between the 3- and
5-positions of the aldehydes (17a, b) (Scheme 4).
Scheme 4a
N
N
iii or iv
ii
CO2Et
CO2Et
N
N
15
R
N
NH2
X
CHO
R
17a, b
15: R = CH(OEt)2
16: R = CHO
1: R = CO2Et
14: R = CHO
i
N
a: X = Br
b: X = NO2
v
N
S
17a, b
CO2Et
CO2Et
18
aReagents and conditions: (i) (a) tritylmethyl chloride, NEt3, CHCl3,
rt; (b) DIBALH, toluene, -70 °C; (c) AcOH/water (5/5, v/v), reflux;
(ii) BrCH2COCO2Et, EtOH, reflux; (iii) Br2, AcOH, rt; (iv) H2SO4,
HNO3, rt; (v) HSCH2CO2Et (1 equiv.), LiOH (2 equiv.), DMF, -10 °C.
N-Tritylation, reduction with DIBAL-H and final removal of the trityl group for compound (1) according
to the literature17 provided the amino aldehyde (14), whose condensation with ethyl bromopyruvate gave
15 and 16 in 18 and 1% yields, respectively. Subsequent bromination and nitration of compound (15)
afforded compounds (17a, b). Treatment of compounds (17a, b) with ethyl thioglycolate and excess
lithium hydroxide in DMF yielded 18 in 23 and 24% yields, respectively. The structure was confirmed by

the presence of a singlet H-7 signal at δ 7.53 and the disappearance of an aldehyde proton signal. To
study further the nucleophilic displacement at the 3-position, we investigated the effect of an electron-
withdrawing group such as formyl group in the 2-position (Scheme 5).
Scheme 5a
N
N
N
iii
+
CHO
CH(OEt)2
CHCl2
: X = H
N
N
N
X
X
X
19
22a,b
21a,b
i or ii
iv
20a,b
N
N
v
: X = Br
a
CO2Et
22a,b
b: X = NO2
S
N
23
CO2Et
N
S
N
v
CHO
vi
CHO
14
N
X
N
CHO
N
CHO
24: X = H
i
S
25a
CO2Et
aReagents and conditions: (i) Br2, AcOH, rt; (ii) H2SO4,HNO3, rt; (iii)
AgNO3, EtOH/water (8/1,v/v), reflux; (iv) MeCN/water (3/1,v/v), HCl,
reflux; (v) HSCH2CO2Et (1 equiv.), LiOH (2 equiv.), DMF, -10 °C; (vi)
(a) ClCH2COCHCl2, DME, rt; (b) EtOH, reflux.
Compounds (20a, b) were obtained by nitration and bromination of 19.19 This route could be used to
prepare substituted 2-carbaldehyde of IP. Compound (20a)18 was further converted under Arbaca’s
conditions19 (silver nitrate in ethanol/water) to give 21a and 22a in 11 and 54% yields, respectively.
Hydrolysis of 21a in MeCN gave 22a in 97%. Aldehyde (22b) was obtained from 20b under similar
conditions. Under the conditions of the substitution reaction, the nitro and bromo compounds (22a, b),
activated by the adjacent carbaldehyde function, were readily displaced and a base-catalyzed cyclization
gave 23 in a very low yield of 1%. This new structure is of obvious pharmacological interest as a
potential immunostimulant by analogy with Levamisol®.20
To develop these annulations on the 2- or 5-positions, we synthesized the dialdehydes (24) and (25a)
from 14 while no nitration of 24 was observed.

However, attempt to extend this method failed, recovering only starting material (25a). We therefore
decided to continue our study as shown in Scheme 6.
Scheme 6a
N
N
ii or iii
i
R
R
1
N
N
26
X
CO2Et
CO2Et
a: X = Br
b: X = NO2
26: R = CHCl2
28a, b: R = CHCl2
29a, b: R = CHO
iv
27: R = CH(OEt)2
N
N
CO2Et
v
29a, b
N
+
N
S
CHO
S
CO2Et
HO
CO2Et
31 (from 29a)
30
aReagents and conditions: (i) (a) ClCH2COCHCl2, DME, rt; (b) EtOH, reflux;
(ii) Br2, AcOH, rt; (iii) H2SO4, HNO3, rt; (iv) AgNO3, EtOH/water (8/1, v/v),
reflux; (v) HSCH2CO2Et (1 equiv.), LiOH (2 equiv.), DMF, -10 °C.
Condensation of 1 with 1,1,3-trichloroacetone in refluxing ethanol gave 26 and 27. The nitration or
bromination of 26, following treatment with silver nitrate, yielded (29a, b) in 39 and 49%, respectively.
The reaction of 29a with ethyl thioglycolate provided 31 as a linear annulation product in 8% yield and
compound (30) in 23% yield, while the reaction of 29b with ethyl thioglycolate afforded only compound
(30) in 24% yield.
In summary, we report new tricyclic systems, fused imidazo[1,2-a]pyridines (13, 18, 23, 30 and 31),
containing sulfur and nitrogen atoms. These tricyclic systems were synthesized by displacement of a
bromo (or nitro) group by ethyl thioglycolate anion and subsequent base-catalyzed ring closure. We have
found that the presence of an electron-withdrawing group in the 2-position is necessary to achieve the
substitution in the 3-position.
EXPERIMENTAL
Instrumentation. Melting points were determined on a capillary apparatus and are not corrected. NMR
13
(400 MHz for 1H or 100 MHz for C) were recorded on a Bruker AC 400 spectrometer using CDCl3 or
DMSO-d6 as solvent. IR spectra were recorded on a Nicolet Impact 410 spectrophotometer. MS spectral

analyses were performed on a Hewlett-Packard 5985B or 5989A instrument. Toluene was dried over Na.
Other dry solvents were stored over molecular sieves.
2-Aminopyridine-6-carbaldehyde (14): A mixture of 2-tritylaminopyridine-6-carbaldehyde17 (400 mg,
1.10 mmol) and aqueous 50% acetic acid (6.5 mL) was refluxed for 1 h to give precipitates which were
removed by filtration. The filtrate was poured onto ice-water and was made basic with aqueous 20%
NH4OH solution. The mixture was extracted with methylene chloride, the combined organic layer was
dried over Na2SO4 and evaporated to dryness to give red solid 14, which were used in the next reaction
without further purification. Yield: 82 mg (61%); mp 121-123 °C (decomp); IR (KBr) ν: 3374, 2924,
1
1701, 1600, 1573, 1457, 1270, 1156, 798 cm–1; H NMR (DMSO-d6) δ: 6.39 (s, 2H), 6.74 (d, 1H, J = 8
Hz), 7.10 (d, 1H, J = 7 Hz), 7.60 (m, 1H), 9.75 (s, 1H). Anal. Calcd for C6H6N2O: C, 59.01; H, 4.95; N,
22.94. Found: C, 59.24; H, 4.93; N, 23.03.
Ethyl imidazo[1,2-a]pyridine-5-carboxylate (2): To a solution of ester (1)11 (5.81 g, 35 mmol) and 5.00
g of NaHCO3 in 250 mL of ethanol were added (12.4 g, 158 mmol) of a solution of chloroacetaldehyde (~
50 wt.% in water). The mixture was refluxed for 9 h and the solvent was removed. Water (200 mL) were
added and the residue was basified with Na2CO3 and extracted with methylene chloride. The combined
organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. Chromatography on
alumina eluting with CH2Cl2 afforded the imidazopyridine (2). Yield: 5.31 g (80%); mp 79-81 °C,
recrystallization solvent: H2O/Ethanol (1/5); IR (KBr) ν: 1720, 1280, 765 cm-1; 1H NMR (CDCl3) δ: 1.44
(t, 3 H, J = 7 Hz), 4.45 (q, 2 H, J = 7 Hz), 7.21 (dd, 1 H, J = 7, 9.5 Hz), 7.80 (s, 1 H), 7.82 (d, 1 H, J = 7
Hz), 7.87 (d, 1 H, J = 8.5 Hz), 8.82 (s, 1 H); 13C NMR (CDCl3) δ: 14.3, 62.0, 114.8, 118.8, 122.2, 122.8,
126.1, 134.8, 146.1, 161.9; MS m/z 190 (M+, 100), 162 (82), 145 (68), 117 (38), 63 (23). Anal. Calcd for
C10H10N2O2: C, 63.16; H, 5.26; N, 14.74. Found: C, 63.32; H, 5.27; N, 14.80.
Imidazo[1,2-a]pyridine-3-carbaldehyde (3): To a solution of ester (2) (0.3 g, 1.58 mmol) in 50 mL of
methylene chloride at –70 °C was added 24 mL (24 mmol) of 1 M DIBAL-H solution in methylene
chloride. After stirring at this temperature for 2 h, 24 mL (24 mmol) of the same DIBAL-H solution was
added. After 1 h, 10 mL of methanol and 2 mL of water were added. The reaction mixture was warmed to
rt, poured into 50 mL of water and extracted with methylene chloride. The combined organic layer was
dried over Na2SO4 and removed under reduced pressure. Chromatography on neutral alumina eluting with
methylene chloride afforded 3: yield (0.18 g, 79%); mp 115-117 °C, recrystallization solvent:
H2O/Ethanol (1/5); IR (KBr) ν: 1670, 1295, 1135, 780, 750 cm-1; 1H NMR (CDC13) δ: 7.35 (dd, 1 H, J =
8.5, 7 Hz), 7.50 (d, 1 H, J = 7 Hz), 7.82 (s, 1 H), 7.95 (d, 1 H, J = 8.5 Hz), 8.99 (s, 1 H), 9.88 (s, 1 H); 13C
NMR (CDCl3) δ: 114.5, 122.3, 124.4, 126.0, 132.1, 136.2, 145.5, 184.6. Anal. Calcd for C8H6N2O2: C,

65.75; H, 4.11; N, 19.18. Found C, 65.49; H, 4.13; N, 19.10.
General Procedure for the Preparation of Esters (7, 8 and 16). To a solution of the appropriate 2-
aminopyridine derivatives (8.55 mmol) in 70 mL of ethanol was added ethyl bromopyruvate (3.85 g,
19.74 mmol). The mixture was refluxed for 5 h and the solvent was removed. The residue was diluted in
water (60 mL) and basified with Na2CO3. The solution was extracted with methylene chloride. The
combined organic layer was dried over Na2SO4, evaporated to dryness under reduced pressure and gave
the required products.
Diethyl imidazo[1,2-a]pyridine-2,5-dicarboxylate (7): (from 111). The residue was chromatographed on
neutral alumina eluting with methylene chloride-ethanol (97/3, v/v) to afford 7 as a white solid: yield
65%; mp 115-117 °C, recrystallization solvent: H2O/Ethanol (1/4); IR (KBr) ν: 1727, 1628, 1518, 1255,
768 cm–1; 1H NMR (CDCl3) δ: 1.48 (m, 6H), 4.51 (m, 4H), 7.34 (m, 1H), 7.87 (d, 1H, J = 7 Hz), 7.96 (d,
1H, J = 9 Hz), 9.43 (s, 1H); 13C NMR (CDCl3) δ: 14.3, 14.5, 61.2, 62.4, 119.3, 120.0, 124.1, 124.2, 126.7,
137.7, 145.8, 161.4, 163.2; MS m/z 262 (M+, 20), 190 (100), 161 (20), 118 (22). Anal. Calcd for
C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C, 59.77; H, 5.35; N, 10.72.
Imidazo[1,2-a]pyridine-2,5-carboxylic acid 2-ethyl-5-methyl diester (8): (from 611). The residue was
chromatographed on neutral alumina eluting with methylene chloride-ethanol (97/3, v/v) to give a white
solid 8: yield: 93%; mp 111-113 °C, recrystallization solvent: H2O/Ethanol (1/4); IR (KBr) ν: 1724, 1628,
1
1440, 1257, 768 cm–1; H NMR (CDCl3) δ: 1.43 (t, 3H, J = 7 Hz), 4.02 (s, 3H), 4.46 (q, 2H, J = 7 Hz),
7.30 (dd, 1H, J = 9, 7 Hz), 7.83 (d, 1H, J = 7 Hz), 7.93 (d, 1H, J = 9 Hz), 9.36 (s, 1H); 13C NMR (CDCl3)
δ: 14.5, 53.1, 61.2, 119.2, 120.2, 124.2, 124.2, 126.4, 137.7, 145.8, 161.8, 163.1; MS m/z 248 (M+, 20),
176 (100), 116 (22), 104 (22), 90 (22). Anal. Calcd for C12H12N2O4: C, 58.06; H, 4.87; N, 11.29. Found:
C, 58.29; H, 4.85; N, 11.33.
Ethyl 5-diethoxymethylimidazo[1,2-a]pyridine-2-carboxylate (15): (from 14). According to the
general procedure for 7, the obtained residue was chromatographed on neutral alumina eluting with
methylene chloride. The first fraction gave 15 as a yellow oil. Yield: 18 %; IR (KBr) ν: 2980, 1742, 1717,
1546, 1266, 1221, 792 cm–1; 1H NMR (CDCl3) δ: 1.19 (t, 6H, J = 7 Hz), 1.38 (t, 3H, J = 7 Hz), 3.57 (q,
4H, J = 7 Hz), 4.41 (q, 2H, J = 7 Hz), 5.58 (s, 1H), 7.05 (d, 1H, J = 7 Hz), 7.21 (dd, 1H, J = 9, 7 Hz), 7.62
13
(d, 1H, J = 9 Hz), 8.47 (s, 1H); C NMR (CDCl3) δ: 14.4, 15.0, 61.0, 61.8, 97.8, 112.4, 116.3, 118.9,
125.3, 134.8, 136.8, 145.8, 163.5; MS m/z 292 (M+, 10), 248 (40), 219 (64), 173 (100), 147 (30), 90 (27),
78 (29). Anal. Calcd for C15H20N2O4: C, 61.63; H, 6.90; N, 9.58. Found: C, 61.87; H, 6.87; N, 9.61. The
second fraction gave ethyl 5-formylimidazo[1,2-a]pyridine-2-carboxylate (16): yield: 1%; mp 121-123
°C, recrystallization solvent: H2O/Ethanol (1/4); 1H NMR (CDCl3) δ: 1.51 (t, 3H, J = 7 Hz), 4.55 (q, 2H,

J = 7 Hz), 7.56 (dd, 1H, J = 9, 7 Hz), 7.68 (d, 1H, J = 7 Hz), 8,16 (d, 1H, J = 9 Hz), 9.62 (s, 1H), 10.01 (s,
1H). Anal. Calcd for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.79; H, 4.60; N, 12.89.
General Procedure for the Synthesis of 19, 24 and 26 by Condensation of 2-Aminopyridine
Derivatives with 1,1,3-Trichloroacetone. To a stirred solution of the appropriate 2-aminopyridine
derivatives (18.07 mmol) in 1,2-dimethoxyethane (DME) (20 mL) was added dropwise a solution of
1,1,3-trichloroacetone (2.88 g, 20.92 mmol) in 5 mL of DME. The mixture was stirred at rt for 4 h. After
filtration, the solid obtained was poured into ethanol solution (70 mL) and heated under reflux for 12 h.
The cooled solution was evaporated and water (100 mL) was added, the suspension made alkaline with
Na2CO3 and extracted with methylene chloride. The combined organic layer was dried over Na2SO4,
evaporated to dryness under reduced pressure. The residue was chromatographed on alumina eluting with
methylene chloride to give the required products.
2-Dichloromethylimidazo[1,2-a]pyridine (19): (from 2-aminopyridine). Yield: 71%; mp 123-125 °C
(lit.,18 127-129 °C).
Imidazo[1,2-a]pyridine-2,5-dicarbaldehyde (24): (from 611). Yield: 5%; mp 169-171 °C,
1
recrystallization solvent: H2O/Ethanol (1/4); IR (KBr); ν: 1700, 1673, 1326, 1048, 788, 592 cm–1; H
NMR (CDCl3) δ: 7.58 (dd, 1H, J = 7, 9 Hz), 7,70 (d, 1H, J = 7 Hz), 8.11 (d, 1H, J = 9 Hz), 9.61 (s, 1H),
13
9.99 (s, 1H), 10.27 (s, 1H); C NMR (CDCl3) δ: 118.1, 124.9, 126.0, 127.4, 133.0, 145.5, 145.9, 184.3,
187.4; MS m/z 174 (M+, 100), 146 (45), 118 (51), 106 (41), 78 (65). Anal. Calcd for C9H6N2O2: C, 62.07;
H, 3.47; N, 16.09. Found: C, 62.31; H, 3.45; N, 16.15.
Ethyl 2-dichloromethylimidazo[1,2-a]pyridine-5-carboxylate (26): (from 111). The first fraction gave
26. Yield: 41%; mp 98-100 °C, (recrystallization solvent: H2O/Ethanol (1/4); IR (KBr) ν: 2976, 1722,
1276, 1258, 1144, 769, 738 cm–1; 1H NMR (CDCl3) δ: 1.48 (t, 3H, J = 7 Hz), 4.51 (q, 2H, J = 7 Hz), 7.00
(s, 1H), 7.33 (dd, 1H, J = 9, 7 Hz), 7.84 (d, 1H, J = 7 Hz), 7.89 (d, 1H, J = 9 Hz), 9.07 (s, 1H); 13C NMR
(CDCl3) δ: 14.2, 62.4, 65.7, 112.9, 119.4, 123.1, 124.0, 126.5, 145.8, 146.1, 161.4; MS m/z 276 (M++ 4,
2), 274 (M++ 2, 14), 272 (M+, 22), 237 (100), 209 (77), 73 (49). Anal. Calcd for C11H10N2O2Cl2: C, 48.37;
H, 3.69; N, 10.26. Found: C, 48.56; H, 3.67; N, 10.30. Further fraction gave a yellow oil ethyl 2-
diethoxymethylimidazo[1,2-a]pyridine-5-carboxylate (27): yellow oil; Yield: 19%; IR (KBr) ν: 2976,
2930, 2889, 1726, 1698, 1272, 1148, 750 cm–1; 1H NMR (CDCl3) δ: 1.30 (t, 6H, J = 7 Hz), 1.47 (t, 3H, J
= 7 Hz), 3.73 (q, 4H, J = 7 Hz), 4.49 (q, 2H, J = 7 Hz), 5.82 (s, 1H), 7.24 (dd, 1H, J = 9, 7 Hz), 7.79 (d,
13
1H, J = 7 Hz), 7.88 (d, 1H, J = 9 Hz), 8.90 (s, 1H); C NMR (CDCl3) δ: 14.3, 15.3, 61.6, 62.1, 98.6,
118.8, 120.5, 122.5, 122.9, 126.2, 145.8, 146.3, 161.8; MS m/z 292 (M+, 1), 248 (22), 219 (100), 191
(56), 78 (16). Anal. Calcd for C15H20N2O4: C, 61.63; H, 6.84; N, 9.58. Found: C, 61.87; H, 6.87; N, 9.64.

General Procedure for the Bromination of Compounds (2, 3, 7, 8, 15, 19, 24 and 26). To a solution of
the appropriate carbonyl derivatives (2.63 mmol) in 8 mL of acetic acid was added dropwise a solution
of bromine (0.53 g, 3.31 mmol) in 2 mL of acetic acid. The solution was stirred at rt for 24 h. The
precipitate was filtered and washed with ether. The filtrate was diluted in 5 mL of water, basified with
Na2CO3 and extracted with methylene chloride. The combined organic layer was dried over Na2SO4,
evaporated to dryness under reduced pressure to give the required bromo products.
Ethyl 3-bromoimidazo[1,2-a]pyridine-5-carboxylate (4a): (from 2). Yield: 82%; mp 129-131 °C,
1
recrystallization solvent: H2O/Ethanol (3/5); IR (KBr) ν: 2622, 1726, 1637, 1280, 1193, 753 cm–1; H
NMR (CDCl3) δ: 1.39 (t, 3H, J = 7 Hz), 4.46 (q, 2H, J = 7 Hz), 7.19 (m, 2H), 7.66 (s, 1H), 7.70 (m, 1H);
13C NMR (CDCl3) δ: 13.9, 62.3, 95.7, 116.47, 120.8, 122.9, 128.9, 136.6, 146.7, 161.6; MS m/z 270
(M++ 2, 51), 268 (M+,48), 189 (30), 161 (75), 145 (83), 86 (66), 84 (100). Anal. Calcd for C10H9N2O2Br:
C, 44.63; H, 3.37; N, 10.41. Found: C, 44.80; H, 3.35; N, 10.45.
Diethyl 3-bromoimidazo[1,2-a]pyridine-5-carbaldehyde (5a): (from 3). Yield: 65%; mp 99-101 °C,
1
recrystallization solvent: H2O/Ethanol (3/5); IR (KBr) ν: 2919, 1675, 1140, 845, 799 cm–1; H NMR
13
(CDCl3) δ: 7.35 (m, 1H), 7.65 (d, 1H, J = 7 Hz), 7.75 (s, 1H), 7.90 (d, 1H, J = 9 Hz), 11.22 (s, 1H); C
NMR (CDCl3) δ: 94.7, 118.9, 123.3, 123.9, 134.6, 137.6, 147.4, 182.5; MS m/z 226 (M++ 2, 21), 224 (M+,
20), 145 (100). Anal. Calcd for C8H5N2OBr: C, 42.85; H, 2.24; N, 12.49. Found: C, 42.87; H, 2.23; N,
12.49.
Diethyl 3-bromoimidazo[1,2-a]pyridine-2,5-dicarboxylate (9a): (from 7). Yield: 37%; mp 106-108 °C,
1
recrystallization solvent: H2O/Ethanol (3/5); IR (KBr) ν: 2979, 1724, 1185, 798, 751 cm–1; H NMR
13
(CDCl3) δ: 1.46 (m, 6H), 4.52 (m, 4H), 7.27 (m, 1H), 7.34 (m, 1H), 7.84 (d, 1H, J = 9 Hz); C NMR
(CDCl3) δ: 13.8, 14.2, 61.4, 62.6, 100.7, 117.6, 121.8, 125.0, 130.2, 135.3, 145.6, 161.3, 161.7; MS m/z
342 (M++ 2, 72), 340 (M+, 70), 270 (100), 233 (23), 217 (63), 196 (39), 150 (24). Anal. Calcd for
C13H13N2O4Br: C, 45.77; H, 3.84; N, 8.21. Found: C, 45.95; H, 3.82; N, 8.24.
3-Bromoimidazo[1,2-a]pyridine-2,5-dicarboxylic acid 2-ethyl-5-methyl diester (10a): (from 8).
Yield: 66%; mp 87-89 °C, recrystallization solvent: H2O/Ethanol (3/5); IR (KBr) ν: 1712, 1511, 1182,
796, 749 cm–1; 1H NMR (CDCl3) δ: 1.42 (t, 3H, J = 7 Hz), 3.99 (s, 3H), 4.45 (q, 2H, J = 7 Hz), 7.22 (dd,
1H, J = 7, 1 Hz), 7.29 (dd, 1H, J = 9, 7 Hz), 7.78 (dd, 1H, J = 9, 1 Hz); 13C NMR (CDCl3) δ: 14.2, 52.9,
61.4, 100.6, 117.7, 122.0, 125.0, 129.9, 135.4, 145.6, 161.8, 161.9; MS m/z 328 (M++ 2, 35), 326 (M+,
33), 254 (79), 196 (72), 136 (100), 115 (100), 103 (70), 92 (43), 76 (61), 64 (100). Anal. Calcd for
C12H11N2O4Br: C, 44.06; H, 3.39; N, 8.56. Found: C, 44.23; H, 3.37; N, 8.59.

Ethyl 3-bromo-5-formylimidazo[1,2-a]pyridine-2-carboxylate (17a): (from 15). Yield: 75%; mp 146-
148 °C, recrystallization solvent: H2O/Ethanol (3/5); IR (KBr) ν: 2924, 2852, 1718, 1685, 1618, 1525,
1252, 1054, 742 cm–1; 1H NMR (CDCl3) δ: 1.53 (t, 3H, J = 7 Hz), 4.56 (q, 2H, J = 7 Hz), 7.47 (m, 1H),
7.69 (d, 1H, J = 7 Hz), 8.01 (d, 1H, J = 9 Hz), 11.30 (s, 1H); 13C NMR (CDCl3) δ: 14.4, 61.9, 99.7, 120.2,
125.0, 125.4, 128.0, 135.7, 146.2, 161.9, 182.3; MS m/z 298 (M++ 2, 19), 296 (M+, 17), 226 (33), 217
(100), 145 (56), 90 (32), 78 (47). Anal. Calcd for C11H9N2O3Br: C, 44.47; H, 3.05; N, 9.46. Found: C,
44.64; H, 3.03; N, 9.46.
3-Bromo-2-dichloromethylimidazo[1,2-a]pyridine (20a)18: (from 2018). Yield: 67%; mp 98-100 °C
(lit.,18 100-102 °C).
3-Bromoimidazo[1,2-a]pyridine-2,5-dicarbaldehyde (25a): (from 24). Yield: 77%; mp 171-173 °C,
–1
1
recrystallization solvent: H2O/Ethanol (3/5); IR (KBr) ν: 2838, 1700, 1673, 1048, 788 cm ; H NMR
(CDCl3) δ: 7.51 (dd, 1H, J = 9, 7 Hz), 7.73 (dd, 1H, J = 7, 1 Hz), 8.00 (dd, 1H, J = 9, 1 Hz), 10.27 (s,
1H), 11.20 (s, 1H); 13C NMR (CDCl3) δ: 99.7, 121.0, 125.3, 125.8, 135.9, 140.7, 147.1, 181.9, 185.8; MS
m/z 254 (M++ 2, 13), 252 (M+, 14), 173 (100), 145 (33), 90 (39), 78 (29). Anal. Calcd for C9H5N2O2Br:
C, 42.72; H, 1.99; N, 11.07. Found: C, 42.89; H, 1.98; N, 11.11.
Ethyl 3-bromo-2-dichloromethylimidazo[1,2-a]pyridine-5-carboxylate (28a): (from 26). Yield: 39%;
1
mp: 97-99 °C, recrystallization solvent: H2O/Ethanol (3/5); IR (KBr) ν: 1738, 1281, 1061, 784 cm–1; H
NMR (CDCl3) δ: 1.37 (t, 3H, J = 7 Hz), 4.44 (q, 2H, J = 7 Hz), 6.95 (s, 1H), 7.25 (m, 1H), 7,29 (d, 1H, J
13
= 7 Hz), 7.76 (d, 1H, J =9 Hz); C NMR (CDCl3) δ: 13.9, 62.6, 63.5, 93.1, 117.5, 121.0, 124.9, 129.6,
143.4, 146.0, 160.8; MS m/z 354 (M++ 4, 16),352 (M++ 2, 36), 350 (M+, 19), 317 (84), 179 (46), 151
(72), 124 (36), 112 (53), 100 (40). Anal. Calcd for C11H9N2O2BrCl2: C, 37.53; H, 2.58; N, 7.96. Found:
C, 37.68; H, 2.56; N, 7.99.
General Procedure for the Nitration of Compounds (2, 3, 7, 8, 15, 19 and 26). To a solution of the
appropriate compounds (10.52 mmol) in 11.2 mL of sulfuric acid was added dropwise 1.8 mL of 65%
nitric acid at –10 °C. The solution was left to stand at rt for 4 h and then poured onto ice. The mixture was
basified with Na2CO3 and extracted with methylene chloride. The combined organic layer was dried over
Na2SO4, evaporated to dryness under reduced pressure to give the required nitro products.
Ethyl 3-nitroimidazo[1,2-a]pyridine-5-carboxylate (4b): (from 2). Yield: 74%; mp 74-76 °C,
1
recrystallization solvent: Ethanol; IR (KBr) ν: 2989, 1727, 1291, 645 cm–1; H NMR (CDCl3) δ: 1.45 (t,
13
3H, J = 7 Hz), 4.51 (q, 2H, J = 7 Hz), 7,71 (m, 2H), 8.01 (m, 1H), 8.58 (s, 1H); C NMR (CDCl3) δ:
14.3, 63.0, 119.3, 121.7, 129.2, 131.1, 134.9, 138.6, 147.0, 161.3; MS m/z 235 (M+, 56), 189 (70), 161

(100), 150 (35), 117 (69), 106 (35), 90 (37), 78 (41). Anal. Calcd for C10H9N3O4: C, 51.07; H, 3.86; N,
17.87. Found: C, 51.27; H, 3.84; N, 17.94.
3-Nitroimidazo[1,2-a]pyridine-5-carbaldehyde (5b): (from 3). Yield: 75%; mp 114-116 °C,
1
recrystallization solvent: Ethanol; IR (KBr) ν: 1689, 1625, 1521, 1459, 1250, 775 cm–1; H NMR
13
(CDCl3) δ: 7.82 (m, 2H), 8.10 (m, 1H), 8.61 (s, 1H), 10.05 (s, 1H); C NMR (CDCl3) δ: 122.6, 123.7,
129.2, 134.5, 135.2, 139.3, 146.5, 180.6; MS m/z 191 (M+, 17), 117 (74), 106 (43), 90 (100), 78 (72).
Anal. Calcd for C8H5N3O3: C, 50.27; H, 2.61; N, 21.98. Found: C, 50.47; H, 2.63; N, 22.06.
Diethyl 3-nitroimidazo[1,2-a]pyridine-2,5-dicarboxylate (9b): (from 7). Yield: 70%; mp 65-67 °C,
1
recrystallization solvent: Ethanol; IR (KBr) ν: 1732, 1630, 1265, 1025, 806 cm–1; H NMR (CDCl3) δ:
13
1.46 (m, 6H), 4.52 (m, 4H), 7.68 (m, 1H), 7.77 (d, 1H, J = 7 Hz), 8.01 (d, 1H, J = 9 Hz); C NMR
(CDCl3) δ: 14.0, 14.1, 62.8, 63.2, 120.5, 122.5, 128.9, 130.0, 132.8, 135.4, 143.5, 160.6, 160.7; MS m/z
307 (M+, 55), 261 (66), 233 (100), 217 (50), 187 (53), 151 (31), 131 (37), 119 (25), 103 (42), 78 (35).
Anal. Calcd for C13H13N3O6: C, 50.82; H, 4.26; N, 13 .68. Found: C, 50.47; H, 4.24; N, 13.73.
3-Nitroimidazo[1,2-a]pyridine-2,5-dicarboxylic acid 2-ethyl 5-methyl diester (10b): (from 8). Yield:
1
85%; mp 87-89 °C, recrystallization solvent: Ethanol; IR (KBr) ν: 2975, 1736, 1239, 833, 752 cm–1; H
NMR (CDCl3) δ: 1.46 (t, 3H, J = 7 Hz), 4.01 (s, 3H), 4.54 (q, 2H, J = 7 Hz), 7.69 (m, 1H), 7.77 (d, 1H, J
= 7 Hz), 8.02 (d, 1H, J = 9 Hz); 13C NMR (CDCl3) δ: 14.0, 53.3, 62.8, 120.6, 122.6, 128.9, 129.7, 132.8,
135.5, 143.5, 160.7, 161.0; MS m/z 293 (M+, 31), 247 (64), 203 (33), 137 (97), 131 (59), 119 (41), 103
(100), 92 (41), 76 (67). Anal. Calcd for C12H11N3O6: C, 49.15; H, 3.78; N, 14.33. Found: C, 49.34; H,
3.76; N, 14.38.
Ethyl 5-Formyl-3-nitroimidazo[1,2-a]pyridine-2-carboxylate (17b): (from 15). Yield: 22%; mp 118-
1
119 °C, recrystallization solvent: Ethanol; IR (KBr) ν: 2926, 1726, 1696, 1267, 812 cm–1; H NMR
(CDCl3) δ: 1.46 (t, 3H, J = 7 Hz), 4.52 (q, 2H, J = 7 Hz), 7.82 (dd, 1H, J = 9, 7 Hz), 7.92 (d, 1H, J = 7
13
Hz), 8.15 (d, 1H, J = 9 Hz), 9.92 (s, 1H); C NMR (CDCl3) δ: 14.1, 62.9, 125.0, 126.3, 128.3, 133.7,
134.2, 134.9, 142.6, 160.4, 181.0; MS m/z 263 (M+, 10), 146 (32), 123 (45), 105 (67), 78 (100), 51 (100).
Anal. Calcd for C11H9N3O5: C, 50.20; H, 3.41; N, 15.96. Found: C, 50.40; H, 3.43; N, 16.02.
2-Dichloromethyl-3-nitroimidazo[1,2-a]pyridine (20b): (from 1918). Yield: 86%; mp 134-136 °C,
1
recrystallization solvent: Ethanol; IR (KBr) ν: 1486, 1369, 1255, 824, 768 cm–1; H NMR (CDCl3) δ:
13
7.42 (t, 1H, J = 7 Hz), 7.66 (s, 1H), 7.78 (m, 1H), 7.97 (d, 1H, J = 9 Hz), 9.43 (d, 1H, J = 7 Hz); C

NMR (CDCl3) δ: 63.0, 117.9, 119.1, 126.0, 127.6, 131.8, 144.7, 147.1; MS m/z 249 (M++ 4, 1), 247 (M++
2, 8), 245 (M+, 13), 175 (20), 130 (21), 78 (100), 51 (52). Anal. Calcd for C8H5N3O2Cl2: C, 39.05; H,
2.05; N, 17.08. Found: C, 39.20; H, 2.04; N, 17.14.
Ethyl 2-dichloromethyl-3-nitroimidazo[1,2-a]pyridine-5-carboxylate (28b): (from 26). Yield: 85%;
1
mp 109-111 °C, recrystallization solvent: Ethanol; IR (KBr) ν: 1740, 1186, 812, 733 cm–1; H NMR
(CDCl3) δ: 1.43 (t, 3H, J = 7 Hz), 4.48 (q, 2H, J = 7 Hz), 7.50 (s, 1H), 7.77 (m, 2H), 8.05 (d, 1H, J = 8
13
Hz); C NMR (CDCl3) δ: 14.2, 63.2, 63.3, 120.2, 121.9, 128.3, 130.3, 131.0, 145.2, 146.0, 161.7; MS
m/z 321 (M++ 4, 2), 319 (M++ 2, 15), 317 (M+, 24), 271 (51), 243 (100), 227 (31), 179 (28), 150 (55), 119
(38), 103 (42), 91(28), 78 (77). Anal. Calcd for C11H9N3O4Cl2: C, 41.53; H, 2.83; N, 13 .21. Found: C,
41.69; H, 2.81; N, 13.26.
General Procedure for Hydrolysis of Compounds (20a, 20b, 28a and 28b). A solution of the
appropriate 2-dichloromethyl derivative (1.78 mmol) in 10 mL of ethanol was mixed with silver nitrate
(1.91 g, 11.21 mmol) in hot water (4 mL). The mixture was boiled (3 h), then cooled at rt, and
concentrated hydrochloric acid was added until pH = 1. The silver salts were removed by filtration under
reduced pressure, and the filtrate was basified with Na2CO3. The mixture was extracted with methylene
chloride. The combined organic layer was dried over Na2SO4, evaporated to dryness under reduced
pressure.
3-bromo-2-diethoxymethylimidazo[1,2-a]pyridine (21a): (from 20a). The residue was
chromatographed on alumina eluting with methylene chloride. The first fraction gave 21a as a yellow oil
1
Yield: 11%; IR (KBr) ν: 2975, 2927, 1718, 1294, 1120, 750 cm–1; H NMR (CDCl3) δ: 1.31 (m, 6H),
3.77 (m, 4H), 5.83 (s, 1H), 6.97 (t, 1H, J = 7 Hz), 7.29 (m, 1H), 7.67 (d, 1H, J = 9 Hz), 8.17 (d, 1H, J = 7
13
Hz); C NMR (CDCl3) δ: 15.4, 62.0, 93.4, 97.6, 113.5, 118.5, 124.0, 125.3, 141.8, 145.3; MS m/z 225
(M+- 74, 57), 197 (21), 90 (30), 78 (100), 63 (24), 51 (41). Anal. Calcd for C12H15N2O2Br: C, 48.16; H,
5.01; N, 9.36. Found: C, 48.35; H, 4.98; N, 9.39. The second fraction gave 3-bromoimidazo[1,2-
a]pyridine-2-carbaldehyde (22a): Yield: 54%; mp 121-123 °C (lit.,18 123-125 °C).
2-Diethoxymethyl-3-nitroimidazo[1,2-a]pyridine (21b): (from 20b). Yield: 21%; mp 69-71 °C,
1
recrystallization solvent: Ethanol; IR (KBr) ν: 2874, 1465, 1369, 1324, 1214, 1054, 751 cm–1; H NMR
(CDCl3) δ: 1.29 (m, 6H), 3.85 (m, 4H), 6.39 (s, 1H), 7.31 (t, 1H, J = 7 Hz), 7.66 (m, 1H), 7.91 (d, 1H, J =
13
9 Hz), 8.45 (d, 1H, J = 7 Hz); C NMR (CDCl3) δ: 15.2, 63.3, 96.1, 117.0, 119.0, 127.6, 129.2, 130.8,
145.2, 149.1; MS m/z 220 (M+- 45, 20), 192 (57), 118 (40), 78 (100), 51 (28). Anal. Calcd for
C12H15N3O4 C, 54.33; H, 5.70; N, 15.84. Found: C, 54.54; H, 5.67; N, 15.90.

Ethyl 3-Bromo-2-formylimidazo[1,2-a]pyridine-5-carboxylate (29a): (from 28a). Yield: 39%; mp 69-
1
71 °C, recrystallization solvent: H2O/Ethanol (3/5); IR (KBr) ν: 2985, 1726, 1702, 1277, 748 cm–1; H
NMR (CDCl3) δ: 1.45 (t, 3H, J = 7 Hz), 4.53 (q, 2H, J = 7 Hz), 7.33 (d, 1H, J = 7 Hz), 7.39 (m, 1H), 8.83
13
(d, 1H, J = 9 Hz), 10.17 (s, 1H); C NMR (CDCl3) δ: 14.0, 62.9, 101.4, 118.4, 122.4, 125.8, 130.4,
140.4, 146.7, 185.8; MS m/z 298 (M++ 2, 64), 296 (M+, 62), 217 (30), 173 (98), 167 (100), 161 (20).
Anal. Calcd for C11H9N2O3Br: C, 44.47; H, 3.05; N, 9.43. Found: C, 44.64; H, 3.03; N, 9.46.
Ethyl 2-Formyl-3-nitroimidazo[1,2-a]pyridine-5-carboxylate (29b): (from 28b). Yield: 49%; mp 79-
1
81 °C, recrystallization solvent: Ethanol; IR (KBr) ν: 2812, 1721, 1684, 1259, 806 cm–1; H NMR
(CDCl3) δ: 1.45 (t, 3H, J = 7 Hz), 4.53 (q, 2H, J = 7 Hz), 7.77 (m, 1H), 7.81 (dd, 1H, J = 7, 1 Hz), 8.08
13
(dd, 1H, J = 8, 1 Hz), 10.58 (s, 1H); C NMR (CDCl3) δ: 14.2, 62.2, 119.9, 121.8, 130.6, 131.5, 131.6,
140.7, 146.9, 161.3, 184.3; MS m/z 263 (M+, 71), 189 (100), 173 (52), 122 (38), 83 (21). Anal. Calcd for
C11H9N3O5: C, 50,20; H, 3,45; N, 15,96. Found: C, 50.40; H, 3.43; N, 16.02.
General Procedure for Hydrolysis of Compounds (21a and 21b). To a well stirred solution containing
the appropriate bromo or nitro compound (4.03 mmol) in 40 mL of MeCN/H2O (3/1, v/v), 0.5 mL of
concentrated hydrochloric acid were added. The mixture was stirred at reflux during 1 h and left to stand
at rt. The mixture was extracted with methylene chloride. The combined organic layer was dried over
Na2SO4, evaporated to dryness under reduced pressure to give the required products.
3-Bromoimidazo[1,2-a]pyridine-2-carbaldehyde (22a): (from 21a). Yield: 93%; mp 121-123 °C (lit.,18
123-125 °C).
3-Nitroimidazo[1,2-a]pyridine-2-carbaldehyde (22b): (from 21b). Yield: 65%; mp 113-115 °C,
1
recrystallization solvent: H2O/Ethanol (3/5); IR (KBr) ν: 1707, 1518, 1214, 655 cm–1; H NMR (CDCl3)
δ: 7.48 (t, 1H, J = 7 Hz), 7.79 (m, 1H), 8.03 (d, 1H, J = 9 Hz), 9.49 (d, 1H, J = 7 Hz), 10.84 (s, 1H); 13C
NMR (CDCl3) δ: 118.8, 120.4, 127.5, 131.8, 141.7, 136.2, 144.5, 184.9; MS m/z 192 (M++ 1, 57), 118
(40), 78 (100), 51 (28). Anal. Calcd for C8H5N3O3: C, 50.27; H, 2.64; N, 21.98. Found: C, 50.47; H, 2.62;
N, 22.06.
General Procedure for Compounds (13, 18, 23, 30 and 31). To a well stirred, cold solution (-10 °C)
containing the appropriate bromo (or nitro) compound (1.32 mmol) and ethyl thioglycolate (327 mg, 0.3
mL) in 3.6 mL of dried DMF was added portionwise lithium hydroxyde (135 mg, 5.62 mmol). The
mixture was left to stand at rt for 3 h, and the solution was poured onto ice-water. The precipitated was
collected to give the required cyclazines compounds.

Diethyl 5-hydroxy-3-thia-1,8b-diazaacenaphthylene-2,4-dicarboxylate (13): Yields: 55% (from 9a);
87% (from 9b); 24% (from 10a); 76% (from 10b); mp 171-173 °C, recrystallization solvent: H2O/Ethanol
1
(1/2); IR (KBr) ν: 3549, 2987, 1701, 1655, 1282, 769 cm–1; H NMR (CDCl3) δ: 1.24 (t, 3H, J = 7 Hz),
1.31 (t, 3H, J = 7 Hz), 3.99 (br s, 1H), 4.12 (q, 2H, J = 7 Hz), 4.26 (q, 2H, J = 7 Hz), 7.00 (m, 2H), 7.14
13
(d, 1H, J = 9 Hz); C NMR (CDCl3) δ: 14.3, 14.5, 59.4, 59.9, 79.6, 109.0, 119.5, 123.3, 127.0, 127.5,
136.2, 144.5, 162.5, 163.0, 165.9; MS m/z 334 (M+, 4), 122 (23), 105 (100), 77 (63), 75 (25), 51 (38).
Anal. Calcd for C15H14N2O5S: C, 53.88; H, 4.19; N, 8.38. Found: C, 54.09; H, 4.20; N, 8.41.
Diethyl 3-thia-1,8b-diazaacenaphthylene-2,4-dicarboxylate (18): Yields: 38% (from 17a); 61% (from
17b); mp > 400 °C, recrystallization solvent: H2O/Ethanol (1/2); IR (KBr) ν: 1735, 1686, 1269, 1048, 784
cm–1; 1H NMR (CDCl3) δ: 1.88 (t, 6H, J = 7 Hz), 4.76 (q, 2H, J = 7 Hz), 4.89 (q, 2H, J = 7 Hz), 6.89 (d,
1H, J = 7 Hz), 7.36 (dd, 1H, J = 9, 7 Hz), 7.46 (d, 1H, J = 9 Hz), 7.53 (s, 1H); 13C NMR (CDCl3) δ: 13.9,
14.0, 60.5, 61.1, 79.0, 113.9, 120.9, 121.2, 125.7, 127.5, 129.4, 134.6, 146.5, 161.2, 161.9; MS m/z 318
(M+, 100), 290 (32), 246 (47), 218 (100), 172 (39), 146 (18), 129 (30), 69 (53), 55 (32). Anal. Calcd for
C15H14N2O4S: C, 56.59; H, 4.43; N, 8.80. Found: C, 56.81; H, 4.41; N, 8.83.
Ethyl thieno[3,2-b]imidazo[1,2-a]pyridine-2-carboxylate (23): yellow oil, yields: 1% (from 22a); 1%
(from 22b); 1H NMR (CDCl3) δ: 1.36 (t, 3H, J = 7 Hz), 4.32 (q, 2H, J = 7 Hz), 6.96 (m, 1H), 6.99 (s, 1H),
7.32 (m, 1H), 7.59 (d, 1H, J = 9 Hz), 8.12 (d, 1H, J = 7 Hz). Anal. Calcd for C12H10N2O2S: C, 58.52; H,
4.09; N, 11.37. Found: C, 58.75; H, 4.07; N, 11.41.
Ethyl 2-formyl-5-hydroxy-3-thia-1,8b-diazaacenaphthylene-4-carboxylate (30): Yields: 23% (from
29a); 24% (from 30b); mp 181-183 °C, recrystallization solvent: H2O/Ethanol (1/2); IR (KBr) ν: 1682,
1665, 1523, 1292, 1248 cm–1; 1H NMR (CDCl3) δ: 1.42 (t, 3H, J = 7 Hz), 3.99 (br s, 1H), 4.39 (q, 2H, J =
7 Hz), 6.69 (d, 1H, J = 7 Hz), 6.84 (dd, 1H, J = 9, 7 Hz), 7.08 (d, 1H, J = 9 Hz), 9.94 (s, 1H); 13C NMR
(CDCl3) δ: 14.1, 63.4, 93.8, 110.2, 121.0, 122.1, 128.2, 131.4, 135.9, 145.9, 154.1, 167.8, 186.7; MS m/z
290 (M+, 100), 244 (93), 217 (53), 188 (36), 84 (20), 49 (21). Anal. Calcd for C13H10N2O4S: C, 53.79; H,
3.47; N, 9.65. Found: C, 54.00; H, 3.45; N, 9.68. The aqueous layer, after extraction with methylene
chloride, was acidified by using acetic acid solution to precipitate diethyl thieno[3,2-b]imidazo[1,2-
a]pyridine-2,8-dicarboxylate (31): Yield: 8% (from 29a); mp 261-263 °C, recrystallization solvent:
1
H2O/Ethanol (1/2); IR (KBr) ν: 1712, 1501, 1388, 1277, 1236, 1195, 1089, 749 cm–1; H NMR (CDCl3)
δ: 1.47 (t, 3H, J = 7 Hz), 1.52 (t, 3H, J = 7 Hz), 4.47 (t, 2H, J = 7 Hz), 4.61 (q, 2H, J = 7 Hz), 7.40 (dd,
1H, J = 9, 7 Hz), 7.87 (dd, 1H, J = 7, 1 Hz), 8.01 (dd, 1H, J = 9, 1 Hz), 8.11 (s, 1H); 13C NMR (CDCl3) δ:
14.3, 14.5, 61.5, 62.9, 117.7, 121.8, 123.7, 124.4, 126.0, 130.5, 134.3, 150.1, 151.5, 162.2, 163.3; MS m/z

318 (M+, 38), 85 (69), 84 (100), 49 (86). Anal. Calcd for C15H14N2O4S: C, 56.59; H, 4.43; N, 8.80. Found:
C, 56.81; H, 4.41; N, 8.83.
5-Ethoxycarbonyl-3-nitroimidazo[1,2-a]pyridine-2-carboxylic acid (11). To a well stirred, cold
solution (ice bath) containing (9b) (498 mg, 1.62 mmol) and ethyl glycolate (0.3 mL, 3.17 mmol) in 3.50
mL of DMF was added portionwise lithium hydroxyde (135 mg, 5.62 mmol). The mixture was left to
stand at rt for 3 h and the solution was poured into ice-water, and acidified with acetic acid to give a solid
which was collected and dried under reduced pressure to give 11. Yield: 171 mg (38%); mp 149-151 °C,
1
recrystallization solvent: H2O/Ethanol (1/2); IR (KBr) ν: 3554, 1716, 1628, 1383, 734 cm–1; H NMR
(CDCl3) δ: 1.32 (t, 3H, J = 7 Hz), 4.39 (q, 2H, J = 7 Hz), 7.92 (m, 2H), 8.21 (dd, 1H, J = 8, 2 Hz,), 12.82
(br s, 1H); 13C NMR (CDCl3) δ: 14.0, 62.8, 121.1, 122.4, 129.2, 130.8, 130.9, 139.3, 144.2, 160.8, 162.7;
MS m/z 279 (M+, 8), 235 (40), 189 (63), 161 (95), 145 (30), 120 (100), 106 (37), 91 (60), 78 (68). Anal.
Calcd for C11H9N3O6: C, 47.31; H, 3.22; N, 15.05. Found: C, 47.50; H, 3.21; N, 15.11.
Tetraethyl 3,3’-Dithiodiimidazo[1,2-a]pyridine-2,2’,4,4’-tetracarboxylate (12). To a well stirred, cold
solution (ice bath) containing (9b) (498 mg, 1.62 mmol) and ethyl 3-mercaptopropionate (0.28 mL, 2.15
mmol) in 3.21 mL of DMF was added portionwise lithium hydroxyde (135 mg, 5.62 mmol). The mixture
was left to stand at rt for 3 h and the solution was poured onto ice-water, and acidified with acetic acid to
give a solid which was collected and dried under reduced pressure to give 12. Yield: 450 mg (95%); mp
146-148 °C, recrystallization solvent: H2O/Ethanol (1/2); IR (KBr) ν: 1735, 1712, 1303, 1194, 1204, 803,
1
788 cm–1; H NMR (CDCl3) δ: 1.36 (t, 12H, J = 7 Hz), 4.30 (q, 8H, J = 7 Hz), 7.06 (d, 2H, J = 6 Hz),
13
7.40 (m, 2H), 7.86 (d, 2H, J = 9 Hz); C NMR (CDCl3) δ: 13.8, 14.3, 61.6, 62.5, 116.6, 120.4, 121.5,
126.9, 131.1, 142.2, 147.0, 161.6, 162.5; MS m/z 586 (M+, 1), 293 (31), 248 (39), 203 (70), 176 (100), 70
(26). Anal. Calcd for C26H26N4O8S2: C, 53.24; H, 4.43; N, 9.55. Found: C, 53.45; H, 4.41; N, 9.58.
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